Originally
published in the journal Medical Hypotheses, 2004;63(5):855-62.

Summary For
a virus to survive and replicate in an organism, it must employ
strategies to evade and misdirect the host's immune response. There
is compelling evidence that the primary immunoevasive strategy
utilized by the SARS virus, like influenza, is to inhibit its host's
corticosteroid stress response. This is accomplished by viral
expression of amino acid sequences that are molecular mimics of the
host's adrenocorticotropin hormone (ACTH). When the host produces
antibodies against these viral antigens, the antibodies also bind to
the host's own ACTH, which limits the host's stress response by
interfering with ACTH's ability to stimulate the secretion of
corticosteroids. This inadequate corticosteroid response provokes
symptoms as a result of a relative adrenocortical insufficiency.
Treatment with corticosteroids can relieve the patient's symptoms of
adrenocortical insufficiency and give them the corticosteroid levels
needed to fight their infection. Similarly, by taking moderate daily
doses of corticosteroids as a prophylactic, it may be possible to
avoid clinical infection with SARS. If
SARS's ACTH mimic strategy never has an opportunity to get started,
SARS's ability to evade its host's immune system while its viral load
is low will be significantly impaired. In this article,
amino acid sequences from the SARS and influenza viruses representing
likely homology to human ACTH are identified. Evidence demonstrating
that ACTH autoantibodies are produced during influenza infection is
also presented. Early
treatment with corticosteroids should lower the dose necessary to
counteract SARS's ACTH autoantibody mechanism. If corticosteroid
treatment is delayed until inflammatory cytokine levels are causing
serious injury, only high doses of corticosteroids are likely to be
effective.

For
a virus to survive and replicate in an organism, it must employ
strategies to evade and misdirect the host's immune response. There
is compelling evidence that the primary immunoevasive strategy
utilized by the SARS virus, like influenza, is to inhibit its host's
corticosteroid stress response. This is accomplished by viral
expression of amino acid sequences that are molecular mimics of the
host's adrenocorticotropin hormone (ACTH). When the host produces
antibodies against these viral antigens, the antibodies also bind to
the host's own ACTH, which limits the host's stress response by
interfering with ACTH's ability to stimulate the secretion of
corticosteroids.

Autoantibodies are
antibodies that have an affinity for an organism's own proteins,
hormones, cytokines, RNA or DNA. Although autoantibodies may be
naturally produced at very low levels, pathological levels are
induced by infectious agents or immunization. When autoantibodies
rise to pathological levels, they can damage or inflame organs and
tissues, disrupt protein and hormone synthesis, or interfere with
hormonal signals and cellular processes (for more information about
autoantibodies, see Davidson and Diamond (1)).

Utilizing
molecular mimicry, an infectious agent directs its host's immune
system against the host by stimulating the creation of antibodies
that crossreact with the host's own molecules. For example, Chlamydia
infection has been shown to cause myocarditis by expressing a
molecular mimic to a segment of the cardiac-specific α
myosin heavy chain molecule (2). Not only is an
infectious agent able to survive better amidst a misdirected immune
response, but if the autoantibodies are directed against significant
molecules, the infection can thrive in a host with a critical system
that is weakened.

ACTH sequence
homology to influenza and the SARS coronavirus

If molecular
mimicry of ACTH increases the virulence of some infectious agents, a
competitive advantage would be conferred to any animal that had a
mutation that made their ACTH antigenically dissimilar while
maintaining ACTH's function, an adaptation for avoiding parasitism.
ACTH consists of 39 amino acids. The first 24 amino acids by
themselves retain steroidgenic activity. The last 18 amino acids of
the molecule are more immunologically active than the whole molecule
and much more active than ACTH1-24 (3).

ACTH25-39
is a less conserved region between species than ACTH1-24 .
If the species differences are the result of successful antigenic
separation, due to selective pressure, then the amino acid positions
of these differences within classes of animals should point to the
antigenically important amino acid positions (probable key residues).
From Table 1, these antigenically important
amino acid positions for mammalian ACTH25-39 are 26, 29,
31, 33, 37 and 39.

Influenza and SARS
contain many examples of amino acid sequences with homology to these
probable ACTH key residues (see Table 2).
Exactly matching 3 of 6 key residues represents likely antigenic
homology, considering that exact matches of only 1 or 2 key residues
has been shown to induce significant T cell activation by molecular
mimics in other viral agents (4-8).
Since, at this time, it is not possible to predict the degree of
antigenic similarity between different sequences, determining which
of the likely sequences is actually an ACTH mimic must be
accomplished by comparing their activation capabilities in T cell
proliferation studies. Furthermore, for the SARS Orf 1AB sequences,
it must be shown that the sequences are expressed.

Table 2 lists 34
matches of 3 of 6 of the probable key residues of human ACTH25-39
in the SARS replicase 1AB protein. There are many matches in the SARS
coronavirus for the ACTH of other species as well. For example, there
are 38 matches of 3 of 6 of the probable key residues of the rabbit's
ACTH25-39 in the SARS replicase 1AB protein (data not
shown). Only one of these is the same as the human matches (at
position 2,437) as just 3 residues are in common between the probable
key residues of rabbit and human ACTH25-39 .

A high frequency
of many mammalian ACTH mimics are also found in the seven currently
published complete amino acid sequences of non-SARS coronaviruses.
The
coronaviruses seem to be repositories of ACTH molecular mimics,
probably collected from other viruses. This may partly explain why
the coronavirus genomes are so large, being the longest known viral
RNA genomes.

Although ACTH
molecular mimics appear to be involved in the virulence of the
influenza and SARS viruses, the determining factor is not clear.
Virulence may relate to the degree of antigenic similarity between
ACTH and its molecular mimic or to the number of active molecular
mimics that the virus employs.

Evidence of SARS
infection has been found in masked palm civets and a Chinese ferret
badger for sale in a market in Guangdong, China (9).
Civets, members of the family Viverridae (mongoose), are weasel-like.
Chinese ferret badgers, similar in appearance to civets, are
classified in the family Mustelidae (weasel), along with the American
mink and the ferret. The ACTH of the American mink has been shown to
be identical to human ACTH. Are these animals susceptible to human
coronavirus or influenza infection because their ACTH possesses
molecular identity to human ACTH? To answer these and other
questions, it would be valuable to determine the ACTH amino acid
sequences for more species, especially to know the ACTH sequence for
more birds.

Evidence for
ACTH antibodies during influenza infection

A systemic stress
response normally produces high serum cortisol and ACTH levels.
Jefferies et al reported that influenza-infected patients had normal
serum cortisol levels but low ACTH levels (10).
These results are difficult to reconcile unless the patients' serum
contained abnormal binding agents to ACTH. For example, if these
patients had autoantibodies to ACTH, the antibodies would have
interfered with the ACTH immunoassay, especially if the
autoantibodies and assay antibodies were competing for the same
antigenic region of the ACTH molecule, which is likely. This would
result in an erroneously low ACTH reading. The assay would only
measure unbound ACTH, as demonstrated in the report by Pranzatelli et
al. of a 9-year-old boy with opsoclonus-myoclonus who was determined
to have ACTH levels of 72 pg/ml and 4.3 pg/ml using conventional ACTH
immunoassay analyses (11). After solid-phase
extraction of the ACTH, the total ACTH level measured by
radioimmunoassay was 3000 pg/ml. ACTH antibodies were subsequently
detected in the boy's serum. Similarly, Jefferies et al's ACTH data
only approximates the free ACTH levels. The measurement of subnormal
ACTH levels of influenza-infected patients is consistent with the
existence of an abnormal binding agent.

Lymphocytes are
involved in the pathogenesis of influenza infection (12).
Injections of anti-lymphocytic antibodies increased the survival rate
of mice infected with influenza A (H2N2). Mice were infected
intranasally with five times a 50% lethal dose of influenza virus.
All saline treated mice died within 13 days. 50% of mice treated
before and after infection with antilymphocyte serum (ALS) survived
more than 15 days after virus infection. The study's authors (Suzuki
et al) conclude, “Assuming that ALS specifically suppresses
immune and normal T lymphocytes it can be inferred that some of these
lymphocytes participate in the influenza disease manifestations.”
The results of this study are consistent with influenza causing T
lymphocytes to induce the production of ACTH autoantibodies.

There are many
symptoms in common between influenza infection and adrenocortical
insufficiency: malaise, fatigue, anorexia, myalgia, headache,
diarrhea and nausea. If influenza virus stimulates the production of
ACTH autoantibodies, after infection, as the autoantibodies interfere
with adrenocortical secretion, the infected individual will enter a
state of relative adrenocortical insufficiency, where their
corticosteroid needs are greater than their available supply.
Furthermore, unlike the increased corticosteroid levels that would be
expected during a systemic immune response, influenza-infected
patients do not have increased cortisol levels (10).
For example, rats injected with sheep red blood cells demonstrated
two- to three-fold increases in corticosteroid levels (13).
It is reported that during the initial phase, before the onset of
respiratory disease, SARS symptoms in adults mimic those of influenza
(14). Therefore, a viral-induced state of
relative adrenocortical insufficiency can explain many of the initial
symptoms of SARS and influenza.

Influenza virus
has been found to be a cytokine dysregulator (15).
The virus induces increased release of inflammatory cytokines, which
disrupts the immune response and can lead to multiple organ
dysfunction, including acute respiratory distress. A necessary
complementary strategy for a cytokine dysregulator would be to
inhibit the host's anti-inflammatory response. By stimulating
production of ACTH autoantibodies, influenza virus is able to limit
the adrenocortical response, allowing the inflammatory cytokine
levels to rise unchecked. Pathological
findings indicate that SARS also employs a strategy of
cytokine dysregulation (16).

Price et al showed
that approximately 48 hours after infecting ferrets with influenza,
fever declines at about the same time as cytokine levels begin to
increase (17). This relief of fever is unlikely
to be to due to the host overcoming the infection. Rather, the
decrease in body temperature could be due to a lower metabolic rate
as a result of relative adrenocortical insufficiency as the infection
succeeds in its ACTH mimicry strategy and proceeds to its next phase
of cytokine dysregulation.

Implications
for SARS treatment

If ACTH
autoantibodies are involved in the pathogenesis of SARS, it indicates
why corticosteroid supplements improve the clinical condition of many
SARS patients, as reported by numerous clinicians (18-20).
The ACTH autoantibodies interfere with the body's attempt to increase
its corticosteroid secretion as part of the body's response to the
infection. Treatment with supraphysiological
doses of corticosteroids gives the patient the high corticosteroid
levels they require to effectively fight the infection and allows the
patient to avoid the symptoms associated with the relative
adrenocortical deficiency resulting from inadequate corticosteroid
levels.

Although many SARS
patients were treated with corticosteroids, often only patients with
severe, unstable or deteriorating clinical conditions were given
corticosteroids. If SARS induces production of ACTH autoantibodies,
then all SARS patients should benefit from early, sustained treatment
with corticosteroids. If patients exhibiting the first signs of SARS
infection are given stress levels of corticosteroids (40-60 mg oral
prednisone twice a day for adults), the patients should feel better
and the virus will be deprived of its primary immunoevasive strategy,
which should make SARS more vulnerable to the immune system. Patients
that are already stressed due to an existing medical condition will
require higher doses. An initial loading dose of corticosteroids may
also prove to be beneficial.

Starting
corticosteroid treatment as soon as possible allows using these lower
doses of corticosteroids. If corticosteroid treatment is delayed
until the patient has become moderately or severely ill, after the
infection has established itself, only large doses of corticosteroids
may be effective. For example, after the infection has begun to
promote the
runaway secretion of inflammatory cytokines, higher doses of
corticosteroids are required to suppress this dysregulation.

Since
corticosteroid supplements compensate for the adrenocortical
insufficiency caused by ACTH autoantibodies, the adrenocortical
insufficiency symptoms may resolve soon after treatment is begun. If
the corticosteroid treatment is decreased or discontinued before the
infection has subsided, these symptoms can easily reappear. This may
explain the reported relapses and continued fatigue of some SARS
patients after decreasing or discontinuing their corticosteroid
treatment. Therefore, if the patient becomes symptomatic as the
corticosteroid dosage is tapered, the dosage should be immediately
raised to a level that was previously effective.

Due
to antigenic competition, during the initial phase of SARS infection,
the antibody response to ACTH antigen can diminish the SARS antibody
response. When interfering ACTH autoantibodies are abundant, ACTH is
hypersecreted, as in Pranzatelli et al's patient with ACTH antibodies
who had total ACTH levels 200 times normal (11).
Since ACTH is more prevalent than SARS antigens, to the immune
system, the ACTH invader appears to be the more serious threat, for
which a larger proportion of resources must be mobilized. This
attenuates the antibody response to SARS. If a sufficient dose of
corticosteroids is given, this will significantly suppress the
pituitary gland's secretion of ACTH and the ACTH antibody response
will abate, which will allow the antibody response to SARS to
increase. Removing the self-antigen and compensating for the lack of
effective ACTH allows the immune system to do its job.

Furthermore,
short-term use of moderate doses of corticosteroids (40 mg of
prednisone per day) may prove to be an effective prophylactic against
clinical infection with SARS. If corticosteroids are an effective
treatment after infection, they may work in the same manner to avoid
clinical infection. An analogy would be the prophylactic use of
antibiotics. If SARS's ACTH mimic strategy never has an opportunity
to get started, SARS's ability to evade its host's immune system
while its viral load is low will be significantly impaired.

The effectiveness
of corticosteroids as a prophylactic against influenza A has been
demonstrated in mice (21). Mice were injected
with non-lethal doses of influenza A, then treated with single
injections of cortisone or daily cortisone treatments. Only the mice
given the prolonged cortisone treatment exhibited suppression of
neutralizing or hemagglutination-inhibiting antibody. Also,
asymptomatic infection while being treated with corticosteroids may
confer immunity.

SARS
containment

Much of SARS
transmission is within hospitals and from known contact with a
SARS-infected individual. If people with known or likely exposure to
SARS are treated with moderate doses of corticosteroids, they will
not avoid SARS infection, but if infected, they should not become
symptomatic or infectious. Prophylactic treatment of these high-risk
individuals could significantly decrease the SARS infection rate. New
infections will only arise from unidentifiable sources. A reasonable
recommended prophylactic corticosteroid dose for adults likely to be
exposed to SARS and exposed adults in quarantine is a low
supraphysiological dose: 20 mg oral prednisone twice a day. Of
course, when discontinuing the corticosteroid treatment, this should
be done by tapering the dosage.

It should be
emphasized that it would not be advantageous for the general
population to employ the use of corticosteroids as a prophylactic
against SARS. Only individuals who have been or are likely to be
exposed to SARS will truly benefit from short-term use of
corticosteroids to avoid SARS symptoms. If there is concern about the
duration of prophylactic corticosteroid use by medical personnel,
these workers can be rotated out of positions of likely exposure to
SARS at appropriate intervals.

There is little or
no hazard in the short-term use of moderate doses of corticosteroids
(60 mg or less of prednisone per day). The principal adverse effects
of corticosteroid use are the development of reversible cushingoid
symptoms (rounding of the face, purple striae, hirsutism, easy
bruising, increased cervicodorsal fat deposition, thinning skin).
These symptoms develop over time and fully resolve upon
discontinuation of corticosteroids. Adequate monitoring of treated
individuals, that is, regular examinations and interviews, is
sufficient to limit any problems arising from the short-term use of
moderate doses of corticosteroids.

Conclusions

As an
immunoevasive strategy, the SARS and influenza viruses utilize
molecular mimicry to inhibit their host's stress response by inducing
the host's immune system to produce ACTH autoantibodies. It is likely
that this strategy is utilized by other infectious agents as well.
Treatment with corticosteroids seems to be the simplest remedy for
counteracting this strategy. Furthermore, short-term, moderate doses
of corticosteroids may be effective as a prophylactic against
clinical infection with SARS.

Early treatment
with corticosteroids should lower the dose necessary to counteract
the infection's ACTH autoantibody mechanism. If corticosteroid
treatment is delayed until inflammatory cytokine levels are causing
serious injury, only high doses of corticosteroids are likely to be
effective.

Acknowledgment

I am extremely
grateful to Dr. Dale M. Edgar for his excellent advice and
significant editorial contribution to this manuscript.